Concern mounting over use of osteoporosis drugs

The long-term safety and effectiveness of bisphosphonates (osteoporosis drugs such as Fosamax and Boniva) have come under scrutiny. This situation has prompted the FDA to conduct a long-term study, which was published on May 9 in the New England Journal of Medicine.

Bisphosphonates are widely prescribed for the treatment of bone loss due to osteoporosis. From 2005 through 2009, more than 150 million prescriptions were dispensed promote bone growth and reduce fracture risk. The condition affects 10 million Americans and another 34 million are at risk for it. Bisphosphonates that have received Food and Drug Administration (FDA) approval have been proven to be very effective for the treatment of osteoporosis in trials conducted over periods of three to four years. In the past year, however, the long-term safety and effectiveness of these drugs has come under scrutiny because of the occurrence of rare but serious side effects such as atypical femur (thigh bone) fractures, osteonecrosis (bone death) of the jaw, and esophageal cancer.

The FDA review was focused on studies in which bisphosphonates had been administered for at least three years; to qualify for the review, fracture date had to be systematically and completely included. Three long term studies were reviewed: the Fosamax Fracture Intervention Trial Long-Term Extension (FLEX); the Reclast Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly–Pivotal Fracture Trial (HORIZON-PFT) extension; and the Actonel Vertebral Efficacy with Risedronate Therapy–Multinational Trial (VERT-MN) extension. In these trials, osteoporosis treatment ranged from six to 10 years.

The FDA reviewers found that the findings in regard to all three bisphosphonates were very similar in terms of average treatment-related increases in bone mineral density through five years. In addition, continuation of therapy beyond five years resulted in maintenance of bone mineral density in the femoral neck and further increases in bone mineral density at the lumbar (lower) spine. In patients who were switched to a placebo, bone mineral density in the femoral neck decreased somewhat during the first one to two years and then stabilized; however, bone mineral density in the lumbar spine continued to increase despite discontinuation of bisphosphonate therapy.

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The FDA reviewers were of the opinion that a more meaningful end point for osteoporosis therapies is the rate of fracture. Each bisphosphonate registration trial (three-to-four-year trials) enrolled 3,000 to 7,500 individuals and focused on the number of fractures that occurred. However, the long-term extension trials, with enrollments ranging from only 164 to 1,233 individuals, were not. Because the FDA was interested in long-term safety and effectiveness, the FLEX trial, with 10 years of bisphosphonate exposure, became the agency’s focus for review.

In the FDA analysis of vertebral fractures (both morphometric (also called asymptomatic or radiographic) fractures and clinical (symptomatic) fractures) that occurred in the two randomized extension trials, the benefit in terms of fracture protection from continued bisphosphonate therapy was inconsistent. In the FLEX trial, the rate of clinical vertebral fractures, but not the rate of morphometric vertebral fractures, was reduced. In the HORIZON-PFT trial, improvement was demonstrated in morphometric vertebral fractures but not in clinical vertebral fractures. An independent analysis of FLEX data revealed a benefit in terms of nonvertebral fractures in a very specific subgroup of patients: those without vertebral fractures at baseline who also had a femoral-neck T score of less than −2.5. (A T-score between -1 and -2.5 signifies osteopenia (weakened bone), and a score less than -2.5 indicates osteoporosis.)

According to the FDA review of data from the FLEX trial, the rates of vertebral and nonvertebral osteoporotic fractures were similar whether the patients continued to receive Fosamax) for up to 10 years (fracture rate: 17.7%) or were switched to a placebo for the extension period (fracture rate: 16.9%). In the time-to-fracture analyses, fracture rates were consistent across treatment groups (Fosamax 5 mg, Fosamax 10 mg, and placebo). When all data on vertebral and nonvertebral osteoporotic fractures with long-term therapy were pooled across the three extension trials (2,496 patients), the fracture rates were found to be relatively constant over time. Pooled data regarding patients who received continuous bisphosphonate treatment for six or more years revealed fracture rates ranging from 9.3-10.6%; however, the rate for patients switched to a placebo was 8.0-8.8%. The investigators noted that these findings raise the question of whether continued bisphosphonate therapy provides additional fracture-prevention benefit, compared to discontinuation of therapy, after five years.

The study authors noted that all labeling for bisphosphonates that are currently FDA approved for treatment of osteoporosis contains an “Important Limitation of Use” statement: “The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.” They noted that in order to optimize the efficacy of bisphosphonates in reducing fracture risk, decisions to continue treatment must be based on individual assessment of risks and benefits and on patient preference. Thus, patients at low risk for fracture (i.e., younger patients without a fracture history and with a bone mineral density approaching normal) may prove to be good candidates for discontinuation of bisphosphonate therapy after three to five years; however, patients at increased risk for fracture (i.e., older patients with a history of fracture and a bone mineral density remaining in the osteoporotic range) may benefit further from continued bisphosphonate therapy.